ABSTRACT Flaviviruses, such as Zika, dengue and West Nile have significant impact on public health with tremendous socioeconomic consequences for a large fraction of the world's population. A large body of epidemiological data suggests that susceptibility to dengue disease is strongly associated with prior flavivirus infection, implicating the presence of cross-reactive, non-neutralizing antibodies as the major disease determinant. This observation has been confirmed in animal disease models, in which passive administration of flavivirus immune sera or flavivirus- reactive monoclonal antibodies enhanced disease severity and resulted in increased mortality. These in vivo studies revealed that the pathogenic activity of antibodies is dependent upon the capacity of their Fc domains to interact with Fc? receptors (Fc?Rs). The currently accepted mechanistic model by which cross-reactive antibodies contribute to disease pathology is based upon the in vitro observation that IgG antibodies mediate infection of Fc?R-expressing cells through increased uptake of virus-IgG complexes in an Fc?R-dependent manner. This phenomenon has been demonstrated in in vitro assays using primary cells or cell lines of the myeloid lineage that express only a limited set of human Fc?Rs. Such experimental conditions do not accurately reflect the complexity and diversity of Fc?R-expressing effector leukocytes present in vivo and it is unclear how these experimental observations could be related to the biological activities of pathogenic antibodies evident in animal disease models and in human populations. More importantly, this simplistic model cannot sufficiently explain why symptomatic dengue disease exhibits so diverse spectrum of clinical phenotypes with varying disease severity and only a small fraction of symptomatic dengue disease patients progress to severe disease and ultimately succumbs to death. It is evident that complex host susceptibility factors exist that influence dengue pathogenesis and determine disease severity. So far, no systematic analysis of the role of Fc?Rs in the antibody- mediated disease enhancement during dengue infection has been performed and the precise contribution of Fc?R-mediated pathways is largely unknown, stemming primarily from the lack of a robust in vivo model system that would mirror precisely the unique complexity of human Fc?R biology. The proposed studies aim to dissect the mechanisms by which Fc-Fc?R interactions mediate ADE in vivo and the Fc effector functions that contribute to dengue disease susceptibility and severity. We anticipate that our findings will significantly advance our understanding of dengue disease pathogenesis and will have broader impact on the study of other flaviviruses, like Zika and yellow fever.